Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With the approval of immune checkpoint blockade(ICB)for TNBC,the addition of pembrolizumab to systemic chemotherapy has become standard of care(SOC)in neoadjuvant systemic therapy(NST)for high-risk early-stage TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated(ON),indicating an ineffective response to treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,the loss of SIAH expression(SIAH^(Low/OFF))in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation(OFF),indicating effective therapy and chemo-sensitive tumor cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

Finite element model validation of bridge based on structural health monitoring——Part Ⅱ:Uncertainty propagation and model validation

Because of uncertainties involved in modeling, construction, and measurement systems, the assessment of the FE model validation must be conducted based on stochastic mea- surements to provide designers with confidence for further applications. In this study, based on the updated model using response surface methodology, a practical model vali- dation methodology via uncertainty propagation is presented. Several criteria of testing/ analysis correlation are introduced, and the sources of model and testing uncertainties are also discussed. After that, Monte Carlo stochastic finite element （FE） method is employed to perform the uncertainty quantification and propagation. The proposed methodology is illustrated with the examination of the validity of a large-span prestressed concrete continuous rigid frame bridge monitored under operational conditions. It can be concluded that the calculated frequencies and vibration modes of the updated FE model of Xiabaishi Bridge are consistent with the measured ones. The relative errors of each frequency are all less than 3.7%. Meanwhile, the overlap ratio indexes of each frequency are all more than 75%; The MAC values of each calculated vibration frequency are all more than 90%. The model of Xiabaishi Bridge is valid in the whole operation space including experimental design space, and its confidence level is upper than 95%. The validated FE model of Xia- baishi Bridge can reflect the current condition of Xiabaishi Bridge, and also can be used as basis of bridge health monitoring, damage identification and safety assessment.